Objective The apolipoprotein E (APOE) ε4 allele may accelerate the progression of HIV disease, and increase the risk for developing HIV-associated neurocognitive disorder (HAND). Whether APOEε4 allele(s) and age may influence brain atrophy in HIV patients is unknown and was evaluated. Methods Automated morphometry on magnetic resonance images, using FreeSurfer analyses, neuropsychological testing and APOE genotyping were performed in 139 subjects [70 seronegative controls (SN); 69 clinically-stable HIV subjects]. Results Compared to SN, HIV subjects had smaller volumes throughout the brain regardless of their HAND status. Compared to APOEε4− subjects, SN controls with APOEε4 had better memory and larger global brain volumes (cerebral white matter and cortex) while HIV subjects with the APOEε4 allele(s) had poorer cognition (verbal fluency, learning, executive function and memory) and smaller cerebral and cerebellar white matter and subcortical structures. Further stratification of age showed that younger (<50 years) APOEε4+SN subjects had larger putamen and cerebral white matter, while younger APOEε4+HIV subjects had poorer performance on verbal fluency and smaller brain volumes [3-way (HIV-status × APOEε4 × Age) interaction-p-values=0.005 to 0.03]. Interpretation These findings suggest that APOEε4 allele(s) may show antagonistic pleiotropy on cognition and brain atrophy in SN controls, but may lead to premature aging with neurodegeneration in younger HIV patients prior to the development of HAND. Potential mechanisms for such interactions may include stronger neuro-inflammation or greater amyloid deposition in younger HIV subjects with APOEε4 allele(s). Early screening for the APOEε4 allele and brain atrophy with morphometry may guide neuroprotective intervention of cognitively normal HIV subjects prior to the development of HAND. Longitudinal follow-up studies and larger sample sizes are needed to validate these cross-sectional results.

Objective-To determine whether brain activation changes in clinically and neurocognitively normal human immunodeficiency virus (HIV)-infected and in HIV-seronegative control (SN) participants over a 1-year period.Methods-Functional magnetic resonance imaging (fMRI) was performed in 32 SN and 31 HIV patients (all with stable combination antiretroviral treatment) at baseline and after 1 year. Each participant performed a set of visual attention tasks with increasing attentional load (from tracking two, three, or four balls). All HIV and SN participants had normal neuropsychological function at both examinations.Results-Over 1 year, HIV patients showed no change in their neurocognitive status or in task performance during fMRI. However, HIV patients showed significant 1-year increases in fMRI signals in the prefrontal and posterior parietal cortices for the more difficult tasks, whereas SN control participants showed only decreases in brain activation in these regions. This resulted in significant interactions between HIV status and time of study in left insula, left parietal, left temporal, and several frontal regions (left and right middle frontal gyrus, and anterior cingulate). Interpretation-Because fMRI task performance remained unchanged in both groups, the HIV patients appeared to maintain performance by increasing usage of the attention network, whereas the control participants reduced usage of the attention network after 1 year. These findings suggest improved efficiency or a practice effect in the SN participants but declined efficiency of the neural substrate in HIV patients, possibly because of ongoing brain injury associated with the HIV infection, despite their apparent stable clinical course.Human immunodeficiency virus (HIV) can invade the brain and cause encephalitis, leukoencephalopathy, axonal damage, and variable neuronal loss.1 These neuropathological processes are accompanied by microglial and glial activation,1 which, in turn, may lead to the release of neurotoxic substances that may further contribute to neuronal apoptosis or neuronal dysfunction. These neuropathological alterations may ultimately lead to the clinical This study extends prior work by evaluating whether performance and brain activation change after 1 year during a set of visual attention tasks. Based on prior cross-sectional results, and our expectation that ongoing neuroinflammation and infection with HIV would lead to chronic and progressive brain injury, we hypothesized that neuroasymptomatic, cognitively stable HIV patients would show load-dependent increases in BOLD signals after 1 year to compensate for decreased neural efficiency while maintaining task performance. In contrast, HIV-seronegative (SN) participants with relatively unchanged neural substrate would show no significant signal changes in fMRI signals and task performances, or possibly signal decreases caused by increased efficiency from practice effects. Patients and Methods Research ParticipantsSixty-three individuals (30 male and 1 female HIV-infect...

Purpose: To determine whether subjects with human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) show altered concentrations of brain glutamate (GLU), and whether lower GLU levels correlate with cognitive deficits.Materials and Methods: GLU concentrations were measured in the basal ganglia, frontal gray and white matter, and parietal gray matter of 45 HIV-positive and 46 ageand-education-matched HIV-negative subjects using echo-time averaged proton magnetic resonance spectroscopy ( 1 H MRS).Results: Compared to controls, HIV subjects with cognitive deficits had lower GLU in the parietal gray matter, while those without cognitive deficits tended to show higher basal ganglia GLU. Lower parietal and frontal gray matter GLU were associated with a greater number of nucleoside reverse transcriptase inhibitors, and were predictive of poorer cognitive performance. Correlations between GLU and cognitive performance, but not the other findings, remained significant after correction for multiple comparisons. Conclusion:Parietal gray matter GLU is lower in HIV subjects with cognitive deficits. This reduction might result from reduced astrocytic reuptake of GLU, secondary excitotoxicity, and mitochondrial toxicity from antiretroviral treatments. The glutamatergic system may play an important role in the pathophysiology of HAND, and brain GLU on 1 H MRS may provide an early surrogate marker for monitoring disease severity and treatment effects.

Background Methamphetamine (METH) abuse continues to be a major illicit drug of abuse. Neuroimaging findings suggest that METH is neurotoxic and may alter various brain structures, but the effect of METH on the aging brain has not been studied. Aim The aim was to determine regional volumes of cortical grey matter in the brains of adult METH-users versus healthy control subjects, and their interaction with age and METH-usage variables. Design Cross-sectional study Setting Magnetic resonance imaging (MRI) Research Center located in a University-affiliated hospital. Participants Thirty-four METH-dependent subjects (21 men and 13 women; ages 33.1±8.9 years), diagnosed according to DSM-IV criteria, and 31 healthy non-METH user comparison subjects (23 men and 8 women ages 35.7±8.4 years). Measurement Regional grey matter volumes were segmented automatically in all subjects and evaluated in relation to age, using high-resolution MRIs at 3.0 Tesla. Findings After adjustment for the effects of cranium size, the METH-users showed enhanced cortical grey matter volume loss with age in the frontal (ANCOVA interaction-p=0.02), occipital (interaction-p=0.01), temporal (interaction-p<0.001), and the insular lobes (interaction-p=0.01) compared to controls, independently of METH-usage patterns. Additionally, METH-users showed smaller grey matter volumes than control subjects in several subregions (dorsolateral prefrontal: p=0.02; orbitofrontal: p=0.03; prefrontal: p=0.047; superior temporal: p=0.04). Conclusions Methamphetamine users appear to show increased cortical grey matter loss with age which raises the possibility of accelerated decline in mental functioning.

Objective-The purpose of this paper was to determine whether antiretroviral medications, especially the nucleoside analogue reverse transcriptase inhibitors, lead to altered brain activation due to their potential neurotoxic effects in patients with human immunodeficiency virus (HIV) infection.Methods-Forty-two right-handed men were enrolled in three groups: seronegative controls (SN, n=18), HIV subjects treated with antiretroviral medications (HIV+ ARV, n=12), or not treated with antiretroviral medications (HIV+NARV, n=12). Each subject performed a set of visual attention tasks with increasing difficulty or load (tracking two, three or four balls) during functional magnetic resonance imaging.Results-HIV subjects, both groups combined, showed greater load-dependent increases in brain activation in the right frontal regions compared to . HIV+ARV additionally showed greater load-dependent increases in activation compared to SN in bilateral superior frontal regions (p-corrected=0.032) and a lower percent accuracy on the performance of the most difficult task (tracking four balls). Region of interest analyses further demonstrated that SN showed load-dependent decreases (with repeated trials despite increasing difficulty), while HIV subjects showed load-dependent increases in activation with the more difficult tasks, especially those on ARVs.Interpretation-These findings suggest that chronic ARV treatments may lead to greater requirement of the attentional network reserve and hence less efficient usage of the network and less practice effects in these HIV patients. As the brain has a limited reserve capacity, exhausting the reserve capacity in HIV+ARV would lead to declined performance with more difficult tasks that require more attention. Prior functional magnetic resonance imaging (fMRI) studies demonstrated increased usage of reserve brain regions during working memory and attention tasks in HIV patients with mild dementia as well as in those who were neuroasymptomatic (Ernst et al. 2002). With effective antiretroviral treatments (ARVs), HIV-infected individuals are living longer, and the full clinical manifestation of HIV-dementia is less common (Dore et al. 2003;Ghafouri et al. 2006). However, the prevalence of a milder form of cognitive impairment appears to be rising among HIV-infected individuals, possibly due to the longer duration of illness and the additional effect of aging in these patients. Although treatment with ARVs typically leads to improved cognitive performance in HIV patients with dementia or cognitive deficits (Larussa et al. 2006;Sacktor et al. 2006;Sacktor et al. 2000), some studies suggest that some ARV treatments may not benefit the cognitive performance of those with lower nadir CD4 counts (Cysique et al. 2006). In addition, patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) develop a varying degree of myopathy or neuropathy after long-term therapy (Dalakas 2001); however, the effects of these drugs on brain function are not well understood. As NRT...

Cannabis is the most abused illegal substance in the United States. Alterations in brain function and motor behavior have been reported in chronic cannabis users, but the results have been variable. The current study aimed to determine whether chronic active cannabis use in humans may alter psychomotor function, brain activation, and hypothalamic-pituitary-axis (HPA) function in men and women. 30 cannabis users (16 men and 14 women, 18 to 45 years old) and 30 non-drug user controls (16 men and 14 women, 19 to 44 years old) were evaluated with neuropsychological tests designed to assess motor behavior and functional MRI (fMRI), using a 3 Tesla scanner, during a visually paced finger-sequencing task, cued by a flashing checkerboard (at 2 or 4 Hz). Salivary cortisol was measured to assess HPA function. Male, but not female, cannabis users had significantly slower performance on psychomotor speed tests. As a group, cannabis users had greater activation in BA 6 than controls, while controls had greater activation in the visual area BA 17 than cannabis users. Cannabis users also had higher salivary cortisol levels than controls (p = 0.002). Chronic active cannabis use is associated with slower and less efficient psychomotor function, especially in the male users, as indicated by a shift from regions involved with automated visually guided responses to more executive or attentional control areas. These brain activities may be attenuated by the higher cortisol levels in the cannabis users which in turn may lead to less efficient visual-motor function.

This study examined the differences in psychiatric symptoms between adult methamphetamine users (n = 46) and control subjects (n = 31), the relationship between psychiatric symptoms and the intensity of methamphetamine craving, and whether psychiatric symptoms were correlated to methamphetamine drug-usage variables (ie, length of abstinence, frequency, duration, and lifetime grams). We found that depressive symptoms on the Center for Epidemiology Studies-Depression (CES-D) and many other psychiatric symptoms on the Symptom Checklist-90 (SCL-90) significantly correlated with craving methamphetamine on the visual analog scale (VAS) for craving. Methamphetamine users had significantly more depressive symptoms (on CES-D) and psychotic symptoms (on SCL-90) compared to controls. There were no significant correlations between psychiatric symptoms and methamphetamine-usage variables. This study provides the first evidence to suggest that depressive symptoms (on CES-D) and psychiatric symptoms (on SCL-90) are strongly associated with the intensity of craving (on VAS) for the drug in methamphetamine users. However, the methamphetamine usage variables had no relationship with psychiatric symptoms. Therefore, methamphetamine users, regardless of their usage patterns, may benefit from treatment of their psychiatric symptoms in order to minimize craving and subsequent relapse to drug use.

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